Molecular Imaging of the Cholinergic System in Parkinson's Disease

Abstract

One of the first identified neurotransmitters in the brain, acetylcholine, is an important modulator that drives changes in neuronal and glial activity. For more than two decades, the main focus of molecular imaging of the cholinergic system in Parkinson's disease (PD) has been on cognitive changes. Imaging studies have confirmed that degeneration of the cholinergic system is a major determinant of dementia in PD. Within the last decade, the focus is expanding to studying cholinergic correlates of mobility impairments, dyskinesias, olfaction, sleep, visual hallucinations and risk taking behavior in this disorder. These studies increasingly recognize that the regional topography of cholinergic brain areas associates with specific functions. In parallel with this trend, more recent molecular cholinergic imaging approaches are investigating cholinergic modulatory functions and contributions to large-scale brain network functions. A novel area of research is imaging cholinergic innervation functions of peripheral autonomic organs that may have the potential of future prodromal diagnosis of PD. Finally, emerging evidence of hypercholinergic activity in prodromal and symptomatic leucine-rich repeat kinase 2 PD may reflect neuronal cholinergic compensation versus a response to neuro-inflammation. Molecular imaging of the cholinergic system has led to many new insights in the etiology of dopamine non-responsive symptoms of PD (more "malignant" hypocholinergic disease phenotype) and is poised to guide and evaluate future cholinergic drug development in this disorder.

Keywords: Acetylcholine; Brain network; Cognition; Dementia with Lewy bodies; Gait; Malignant phenotype; Motor; Parkinson's disease.

Figure 1.

ACh nerve terminal figure illustrating pre-synaptic and post-synaptic molecular cholinergic imaging targets.

Figure 2.

Multiligand cholinergic PET study in a single PD subject using [¹¹C]-PMP AChE (top row), [¹⁸F]-FEOBV VAChT (middle row), and [¹⁸F]-Flubatine α4β2 nAChR (bottom row) PET. Columns A-B: all three tracers show uptake in the cortex, with relatively more increased uptake in the anterior frontotemporal cortices. Columns C-D: both [¹¹C]-PMP and [¹⁸F]-FEOBV show intense uptake in the striatum and thalamus. [¹⁸F]-Flubatine shows intense uptake in the thalamus but only limited uptake in the striatum. Columns E-G: [¹⁸F]-FEOBV shows intense uptake in the cerebellar vermis especially while [¹¹C]-PMP has intense uptake in the entire cerebellum. [¹⁸F]-Flubatine shows lower and more diffuse uptake in the cerebellum. All three tracers show uptake in the pontine region, with [¹¹C]-PMP > [¹⁸F]-FEOBV > [¹⁸F]-Flubatine.

Figure 3.

Cortical cholinergic denervation is a major neurodegeneration associated with progressive declines across the spectrum of cognitive impairment in PD. The relative frequencies of significant neocortical hypocholinergic activity increases from about 25% in patients with no or minimal cognitive impairment to over 85% in patients with a global cognitive Z-score of 2 standard deviations below the normal range of cognitive performance (N. I. Bohnen et al., 2015).